Synthesis And Insecticidal Activity Of Derivatives Of 4’-demethyl Epipodophyllotoxin(E-ring Containing Quinoxaline) And 4-alkyloxy-2’(2’,6’),2α-multihalogen-substituted Podophyllotoxin

As is well-known,pesticide is an important part of agriculture.Development of the efficiency,low residue and environmentally friendly pesticides is the key to discover new agrochemicals.Structural optimization based on natural active substances as lead compounds has become a significant way to innovate new pesticides.Podophyllotoxin,isolated from the roots and rhizomes of some Podophyllum and Juniperus species,is a promising lead compound for development of insecticidal agents,in addition to an important antitumor drug precursor.In order to discover novel podophyllotoxin derivatives as new insecticidal agents,and clarify their structure-activity relationships(SARs),six series(ninty-eight new compounds)of derivatives of podophyllotoxin and 4’-demethylepipodophyllotoxin were designed and synthesized by introducing the active groups on the basis of our previous studies.Meanwhile,their antifeedant and insecticidal activities were tested against the pre-third-instar larvae of oriental armyworm,Mythimna separata Walker in vivo at the concentration of 1 mg/m L by the leaf-dipping method.Moreover,their SARs were also discussed.It will pave the way for further research and development of podophyllotoxin derivatives as new insecticides.The main results were obtained as follows:(1)Fourteen novel 4β-acyloxy derivatives of 4’-demethylepipodophyllotoxin containing quinoxaline were synthesized by modifying the C and E rings.Their structures were well determined and characterized by 1H NMR and 13 C NMR spectroseopies,and the steric configuration was unambiguously confirmed by single crystal X-ray diffraction analysis.Compounds IIh and IIj displayed more pronounced insecticidal activity than toosendanin.It indicated that the insecticidal activity would be enhanced when the substituent R was a fatty chain of moderate length or a substituted phenyl group.(2)Sixty derivatives containing nitroquinoxaline were prepared by modifying 4’-demethylepipodophyllotoxin and E ring-chlorinated 4’-demethylepipodophyllotoxin.Their structures and stereochemical configurations of all the compounds were confirmed by 1H NMR,13 C NMR and X-ray crystallography.Among all derivatives,III-4i exhibited the best potent stomach toxicity.The preliminary SARs showed that introduction of the butyryloxy or capryloyloxy group at the C-4 position could result in the potent compounds.(3)Nine novel oxime sulfonate derivatives of 4’-demethylepipodophyllotoxin-based quinoxaline were synthesized,and their structures were identified by 1H NMR,IR and HRMS spectroseopies.The trans configuration of the C=N bond was determined by single crystal X-ray diffraction analysis of compound IV-3c.Most compounds exhibited more pronounced insecticidal activity than or comparable to toosendanin.It demonstrated that introduction of methyl,ethyl or nitro group on the phenylsulfonate was of great benefit to the insecticidal activity.(4)By modifying the C,D and E rings of podophyllotoxin,twelve 4α/β-alkyloxy-2’(2’,6’),2α-multihalogen-substituted podophyllotoxin derivatives and three by-products with C ring aromatization were obtained.Their structures were well characterized by 1H NMR,13 C NMR,IR,HRMS,specific rotation and melting points,and the stereochemical configurations were further confirmed by X-ray crystallography.Compounds V-5a,V-5f,V-5i and V-5j exhibited more promising insecticidal activity than or comparable to toosendanin;especially V-5a showed the best potent insecticidal activity.This indicated that introduction of the benzyloxy or cyclopentanoxy group at the C-4 position of multihalogen-substituted podophyllotoxin could afford the more potent compounds.(5)Podophyllotoxin,2’-chloropodophyllotoxin and 2’-bromopodophyllotoxin were firstly converted to the corresponding picropodophyllotoxins,which were then oxided in the presence of CrO3,followed by reaction with hydroxylamine hydrochloride to produce three oximes.Finally,three lactam derivatives of picropodophyllotoxins were obtained by Beckmann rearrangement reaction.Their structures were characterized by 1H NMR,IR,HRMS,and melting points.The three-dimensional structure of V-12 a was unambiguously confirmed by single crystal X-ray diffraction analysis.Moreover,the Beckmann rearrangement reaction,a trans-rearrangement,was further testified.It showed that the lactam derivatives containing a halogen atom in the E ring,exhibited the pronounced insecticidal activity.